The presence of a normal amount of libido, defined as the urge to engage in sexual activity, is an important component of an individual's well-being. In both men and women the primary naturally occurring hormone responsible for libido is testosterone. In males, the baseline testosterone level is a relatively constant throughout life, decreasing slowly in old age. Abnormally low levels of testosterone also Occur in male hypogonadism and are similarly associated with lack of libido and inability to produce or sustain erections. In contrast, women elaborate testosterone only as part of the process of ovulation. Each maturing follicle produces testosterone at the mid-point of the menstrual cycle, consistent with observations that female libido peaks with ovulation. As a woman ages, the number of maturing follicles per month decreases, and there is a decreasing total amount of testosterone produced. A common complaint of post-menopausal women is decreased libido. This decrease in libido is characterized by a lack of interest in sexual intercourse, the lack of ability to achieve orgasm, or decrease in intensity of orgasm. It is important to note that this decrease in libido is often associated with a profound sense of loss of a once normal and active interest in sexual activity. Low levels of testosterone in, e.g., hypogonadal men are associated with lack of libido and absence of erections. They respond to therapy with exogenous testosterone (Cunningham et al., J Clin Endocrinol Metab, (March 1990) 70:792-7; Behre et al., J Clin Endocrinol Metab, (November 1992) 75:1204-10; and women also respond to testosterone therapy, see Tuiten et al., Arch. Gen. Phychiatry, (February 2000) 57:149-153.
Clinicians frequently confronted with the problem of managing female patients presenting with decreased libido have limited tools to address the problem. Testosterone is available as an oral preparation and can be given, for instance, in combination with estrogen to restore testosterone levels. However, the replacement of the once pulsatile endogenous delivery of testosterone with the sustained blood level of the hormone produces unwanted side effects. Women taking testosterone for a few weeks typically begin to complain of the emergence of secondary sexual characteristics such as unwanted body hair, oily hair, and, with prolonged a use, deepening voice. For this reason, oral testosterone replacement therapy is not a practical solution for most patients with decreased libido.
Other forms of testosterone replacement therapy for women are being explored. A transdermal patch capable of delivering a steady rate of testosterone is being tested for use in women. As with oral testosterone replacement therapy, the study state blood levels of testosterone produced via transdermal delivery are likely to be associated with the same side effect profile issues.
It is recognized that testosterone in males and females decreases with age (Expert Opin. Pharmacother 2003 February; 4(2):183-90; Human Biology, May 1980, Vol. 52, No. 2, pages 181-01,91), and that sexual motivation in men with low testosterone as well as mood and well-being in post-menopausal women is associated with the levels of exogenously introduced testosterone (Psychosomatic Medicine volume 47, No. 4, 1985). Further, providing intravenous testosterone to men and women as part of clinical studies is known (Am Heart J 2002 February; 143(2):249-56; American Journal of Obstetrics and Gynecology, December 1986 pages 1288 to 1292).
Various formulations of testosterone are currently commercially available to treat sexual dysfunction in men. A transdermal patch for men is sold by Alza Corporation under the name of Testoderm®. An injectable for intramuscular injectable is sold by Bristol-Meyers-Squibb Company under the name Delatestryl®, and by Star under the name Virilon® IM. While these dosage forms may increase steady state levels of testosterone in men, they do not result in the physiologically correct pulsatile release that occurs in men with normal testosterone production. A bolus delivery of testosterone provides an approximation to the pulsatile delivery yielding short brief peaks that can provide the physiological stimulus for increase of sexual desire and improved erectile function.
Current therapies and those under development for erectile dysfunction (ED) include phosphodiesterase (PDE) inhibitors (e.g., Viagra (sildenafil), Cialis), dopamine receptor agonists (e.g., apomorphine), melanocortin receptor agonists, intracavernous therapies (e.g., alprostadil, papaverine, phentolamine, vasoactive intestinal peptide), growth hormone-releasing peptide receptor agonists, 5-hydroxytryptamine (5-HT; serotonin) receptor agonists, alpha-adrenoceptor antagonists, topical therapies (e.g., alprostadil), guanylyl cyclase activators, rho-kinase antagonists and inhibitors of neuropeptide Y.
In cases where a single therapy for ED is ineffective, combination therapy may be effective, especially when two or more mechanisms the drugs affect different sites of action are simultaneously employed. For example, the combination of a drug that acts centrally, e.g., on the central nervous system (CNS), with a drug that acts peripherally has been proposed (Andersson and Hedlund, Int. J. Impot. Res. 14(Suppl.1): S82-S92, 2002). For example in a rat model, the erectile response to apomorphine, which acts via the CNS, has been prolonged by sildenafil, which acts peripherally (Andersson et al. J. Urol. 161: 1707-12, 1999). The use of a combination therapy involving inhaled testosterone, which acts on the CNS, with any other class of treatment, whether it acts centrally or peripherally, having therapeutic potential may be more effective than either treatment alone.